Arterial load and its impact on wall myocardial stress, dysfunction and heart failure risk in the general population

The present thesis deals with the heart (left ventricle) and the arteries and is the result of various closely related projects that aimed to assess different aspects of arterial properties, ventriculararterial interactions, their role in myocardial afterload, their relationship with myocardial dysfunction and the risk of incident heart failure. Although the presented projects follow a line of work and lead to a well pre-defined goal, the thesis is written (according to publication layout) as a series of semi-independent chapters, each with its own introduction, methods, results and discussion section. The thesis begins with two review chapters that focus on the non-invasive assessment of left ventricular (LV) afterload through the analysis of proximal aortic pressure-flow relations, written in a format that is directed to clinical cardiologists and specialists in non-invasive imaging (echocardiography, CT, MRI), who may or may not have a deep understanding of the physics of fluid dynamics. Aortic input impedance depends entirely on vascular properties, rather than LV function. However, the myocardium itself does not directly sense input impedance. Therefore, a more direct assessment of what the myocardium might sense during contraction (afterload) may be derived from computations of wall stress, which in turn results from myocardial contraction and the interaction of the pumping LV with the systemic arterial input impedance. We present work directed toward the non-invasive characterization of time-resolved myocardial wall stress patterns using a novel combination of speckle-tracking echocardiography (instantaneous geometry) and arterial tonometry (instantaneous pressure). Consistent with physiologic principles, we report a very early-systolic peak in wall stress that diminishes in mid- and latesystole due to progressive decrease of LV cavity size that occur during ejection. We demonstrate that there is a marked shift in the pressure-stress relationship in mid-systole, such that wall stress at late-systole is low relative to even late-peaking pressures, a sequence of events that seems ideal to protect the myocardium (to some extent) from excessive late systolic wall stress. We subsequently applied these methods developed for studying a large epidemiological human cohort (Asklepios study population). Given the complex nature of time-resolved wall stress, we aimed to assess which arterial properties are most relevant to early and late systolic wall stress in humans. This goal required careful consideration of the effect of body size. We present work in which we aimed to determine optimal methods for allometric normalization of indices of arterial properties and LV mass, through the derivation of adequate allometric powers to describe (and adjust for) the non-linear relationships that exist between indices and various commonly used measures of body size (height, weight, body surface area). We performed analogous work for LV mass and demonstrate that the appropriate allometric exponents are different than the present accepted standard, which hadn’t accounted for the important confounding effect of gender. Once we were able to confidently characterize the relationships between arterial properties and body size, we assessed the relationship between arterial properties and time-resolved systolic wall stress in humans. We found that there are discrete relationships between arterial load components and wall stress, such that both early and late ejection-phase wall stress are strongly related to systemic vascular resistance, that early systolic stress is modestly related to aortic characteristic impedance, and that the wave reflection magnitude is an important determinant of the late systolic wall stress and accordingly the myocardial loading sequence (early vs. late systolic wall stress). We also present work that assessed the relationship between early vs. late myocardial wall stress and parameters of myocardial contraction and relaxation that have well established physiologic and prognostic value. Our findings indicate that in unselected middle-aged adults, greater early (and/or peak) systolic wall stress was associated with greater longitudinal systolic function and enhanced early diastolic relaxation of the myocardium. In contrast, late systolic myocardial wall stress was independently associated with decreased early diastolic relaxation and decreased longitudinal systolic function, supporting a role for the myocardial loading sequence as a determinant of systolic and diastolic myocardial function. Given (1) the role of the reflected wave as a determinant of myocardial loading sequence, (2) the physiologic results obtained in the Asklepios cohort and (3) previous publications that link the loading sequence with LV maladaptive remodeling, hypertrophy and dysfunction, we set the goal of testing the hypothesis that a prominent reflected wave is associated with an increased risk of heart failure in a human population. The final chapter of the thesis presents work in which we demonstrate a strong independent relationship between reflection magnitude and incident heart failure risk in an ancillary study to the multiethnic study of atherosclerosis (MESA). We believe that these data and the line of work presented here identify an important novel independent risk factor for new-onset heart failure among adults in the general population who are free of clinically apparent cardiovascular disease. The thesis concludes with a brief perspective of how these initial findings can be addressed in future research and attempts to identify some questions and goals for future research in the field. Finally, we include three published editorials commenting on our work as supplemental material